Aberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK-) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK- ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters. Furthermore, we uncover a close relationship between global ALCL DNA methylation patterns and those in distinct thymic developmental stages and observe tumor-specific DNA hypomethylation in regulatory regions that are enriched for conserved transcription factor binding motifs such as AP1. Our results indicate similarity between ALCL tumor cells and thymic T cell subsets and a direct relationship between ALCL oncogenic signaling and DNA methylation through transcription factor induction and occupancy.G.E. was funded by the Austrian Science Foundation (FWF) (P 27616 and V 102). M.R.H. was supported by a L’Oréal for Women in Science grant. S.D.T. receives funding from Bloodwise (formerly Leukaemia and Lymphoma Research). L.K. has been funded by the FWF (P 26011 and P 29251), as well as the MSCA-ITN-2015-ETN ALKATRAS (No. 675712). D.J.W. is a paid consultant for Zymo Research Corporation.This is the final version of the article. It first appeared from Elsevier (Cell Press) via http://dx.doi.org/10.1016/j.celrep.2016.09.01
